Patent Literatures (PTLs) 1 and 2 made detailed descriptions of the demerits in conventional inactivated vaccines or toxoids, as well as the current states with regard to the development of mucosal vaccines and immunoadjuvants.
As described in PTLs 1 and 2, the requirement of switching from a conventional vaccine of being inoculated subcutaneously or intramuscularly to a mucosal vaccine inducing the production of an IgA antibody on mucosa which is a natural viral infection route, is widely and profoundly recognized. Especially as a next generation vaccine in the 21st century, a mucosal vaccine inducing IgA antibody production, topical immunity or mucosal immunity is desired to be developed and brought into practical use all over the world, but it has not be achieved yet.
In response to these problems, the present inventions have invented an, antigen-drug (AD) vehicle, which is a complex of a pulmonary surfactant protein B and/or a pulmonary surfactant protein C and a lipid(s), and a mucosal vaccine consisting of this AD vehicle and an antigen (PTL 1). The present inventors also found that by adjusting the weight ratio V/A of the AD vehicle amount (V) to the antigen amount (A), the selective production of an IgA antibody and the production of both IgA and IgG antibodies are convertible, and then developed a mucosal vaccine based on such action mechanism (PTL 2). PTLs 1 and 2 also disclose the effectiveness of fragments (peptides) of the pulmonary surfactant proteins B and C.
In addition, as a result of a study on various variants of pulmonary surfactant protein fragments for their antibody production enhancing effects, the present inventors have invented an AD vehicle [hereinafter abbreviated as AD vehicle (a)] comprising as a component a synthetic peptide KnLm (wherein n is 4 to 8 and m is 11 to 20) which, in spite that it is a smaller-sized peptide than the partial peptides disclosed in PTLs 1 and 2, has a potent antibody production-inducing or -enhancing effect, especially for an exclusive production of a secretory IgA antibody as well as an excellent and effective inductory effect on the production of both secretory IgA and blood IgG, and a mucosal vaccine consisting of this AD vehicle (a) and an antigen (PTL 3).
While the inventions of PTLs 1 to 3 relate to a mucosal vaccine having broad utility, the effectiveness was confirmed by using an influenza virus.
On the other hand, the mucosal vaccine has been investigated for respiratory disease-causing viruses other than the influenza virus. Among such viruses, an RSV is a major virus causative of a common cold syndrome, and is one of the viruses the immune for which is difficult to acquire because its infection occurs many times in a life.
The RSV infection causes bronchiolitis and pneumonia in infants, elders and immunodeficiency patients, and especially about 30% of primary RSV infection cases in infants lead to lower airway inflammation. Among such cases, 1 to 3% progress to a severe state requiring hospitalization, because of which a vaccine therefor is highly demanded.
The RSV is an RNA virus belonging to Paramyxoviridae, and can roughly be grouped into subtype A and subtype B. It is known that, on the surface of the virus, there are F protein important for fusion with a host cell (Non Patent Literature (NPL) 1), G protein involved in adhesion to a host cell (NPL1), and SH protein, Accordingly, a whole viral particle or these proteins have been studied as antigens for many RSV vaccines.
In a usual method, the first option for a vaccine against a virus is a formalin-inactivated vaccine. Since such a method exhibited a sufficient vaccine effect against the influenza virus, formalin-inactivated vaccines have been employed for a long time.
While the formalin-inactivated vaccine was tested in 1960's also against the RSV, it resulted not only in the lack of the vaccine effect on the RSV but also in serious side effects in infants, unlike the cases against the influenza virus (NPL2).
Thereafter, the RSV vaccine was subjected to researching for split vaccines which are a mixture of a part of the virus constituents and an adjuvant (PTL 4, PTL 5). Until today, attempts to develop the RSV vaccines involved an attempt to specify the antigen having an infection preventing ability, a development of an effective adjuvant and a development of vaccine inoculation methods. Previous reports include a report of infection-preventing antibody induction by a novel inactivation method (NPL3), a report that the RSV membrane fusion F protein is effective as an antigen (NPL4) and a report that the RSV G protein is effective as an antigen (NPL5). In the current state, the results may differ depending on the method for administrating an RSV antigen as a vaccine and on the combination of the adjuvant to be added with the antigen. Nonetheless, there is no RSV vaccines approved on marketed yet, because of their insufficient vaccine effect or side effects.